The long-term objectives of the proposed study are to elucidate the mechanisms by which insecticides exert their toxic actions on mammals. Specific attention is focused on the mechanisms underlying the interactions of neuroactive insecticides with ion channels by using patch clamp techniques as applied to mammalian neurons which include mouse neuroblastoma cells, rat dorsal root ganglion neurons, and rat hippocampal and cortical neurons. Two classes of insecticides will be studied. One class includes pyrethroids and DDT which are different in chemical structure but are similar in the mode of action. The other class includes cyclodienes and lindane. Pyrethroids and DDT are known to act on the neuronal sodium channels thereby causing hyperactivity and convulsions in animals. Detailed mechanisms whereby these insecticides modify the sodium channel activity will be studied with special reference to the negative temperature dependence, tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels, comparison between pyrethroids and DDT, and selective block of pyrethroid-modified sodium channels by certain local anesthetics. The effects of pyrethroids on calcium channels, GABA receptor-channel complex and excitatory amino acid complex have been controversial, and detailed patch clamp experiments will be performed to clarify the significance in toxicity. Cyclodienes and lindane are known to block the GABA receptor-channel complex, yet no detailed mechanisms have been elucidated. The study will address the questions of single channel modification, exact site of action on the receptor-channel complex, comparison of lindane isomers, voltage and use dependence of action, interactions of polyvalent cations, and tissue specificity. The proposed study will provide useful and critical information for development of newer and safer insecticides and for treatment of insecticide intoxication in humans.